The long-term objective is to design a specific carrier system for delivering anticancer drugs to tumor cells. Recent progress in the development of long-circulating liposomes has overcome some difficult hurdles previously experienced with this approach. These novel liposomes are covalently coated with long-chain polyethylenglycol (PEG) or containing the ganglioside Gm1. Due to the steric barrier on the surface the liposomes are resistant to opsonin adsorption and hence show reduced uptake by the reticuloendothelial system and stay in the circulation for prolonged periods of time. A significant fraction (up to 20%) of the inject dose can extravasate the tumor vasculature and accumulate mainly in the interstitial space inside the tumor. Since the drug containing liposomes are not taken up by the tumor cells, probably due to the presence of the steric barrier, their drug delivery potential is not fully realized. The first aim of the project is to design liposomes with PEG chains attached via labile linkers so that the chains may fall off from the liposome surface after all the liposomes have arrived at the tumor. These new liposomes may have an improved chance to interact with the tumor cells. The second aim is to take advantage of a long- circulating, pH-sensitive liposome formulation to deliver liposomes have already been constructed in the lab. Cytotoxic drugs which by themselves do not penetrate into cells will be delivered to the interior of tumor cells using these liposomes. The last aim is to prepare PEG- immunoliposomes but the antibody molecules will be attached to the tips of the PEG chains to avoid steric hindrance. The immunoliposomes should efficiently bind to the tumor cells. Murine colon carcinoma MC38 and a derivative expressing the transfected human carcinoembryonic antigen cDNA will be used as solid tumor models. The derivative cells, MC38-CEA2, will be used in the immunoliposome studies by using a monoclonal antibody to the human CEA. Adriamycin and other anticancer drugs will be tested in these novel targeting systems for their improved antitumor activities.